Synthesis of s-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate

ABSTRACT

The present invention provides a convenient process for the preparation of S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1, comprising
         (a) treating 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene, a compound of formula 3 with alkali metal carbonate-alcohol system to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid, a compound of formula 4;   (b) reacting the compound of formula 4 with bromofluoromethane to yield the compound of formula 1.

The present invention relates to a convenient process for thepreparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,a compound of formula 1. S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,commonly known a fluticasone propionate (INN), is used as ananti-inflammatory and antipruritic agent.

PRIOR ART

U.S. Pat. No. 4,335,121 (referred to herein as the '121 patent)discloses the compound of formula 1 and its preparation. It disclosesthe process of its preparation by treating6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, a compound of formula 2 withdimethylthiocarbamoyl chloride to yield17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene,a compound of formula 3,

which is decomposed by refluxing in diethylamine to the thioic acid offormula 4. The compound of formula 4 is then reacted withbromochloromethane in presence of sodium bicarbonate to give achloromethyl ester of formula 5. The compound of formula 5, is convertedto an iodomethyl ester by halogen exchange and subsequently treated withsilver fluoride to yield the compound of formula 1. This process ofpreparation of the compound of formula 1 is very tedious, lengthy, andinvolves use of expensive and sensitive chemicals, viz. silver fluoride.This prior art teaches the use of ammonia, a primary amine or morepreferably a secondary amine such as diethylamine or pyrrolidine forconversion of compound of formula 3 to compound of formula 4. However,the yield obtained with use of secondary amines such as diethylamine ispoor.

PCT publication WO 01/62722 (equivalent of which is U.S. 2002/0133032A1)discloses the method of preparing the compound of formula 1 by reactinga compound of formula 2 with dimethylthiocarbamoyl chloride and molarequivalents of sodium iodide in 2-butanaone to get compound of formula3. The compound of formula 3 is then reacted with a hydrolyzing agentsuch as sodium hydrosulfide to generate the sodium salt of formula 4,which can be alkylated in-situ with chlorofluoromethane to yield thecompound of formula 1 or alternately can be acidified to obtain thecompound of formula 4, which can be isolated and converted to compoundof formula 1 by alkylation with chlorofluoromethane. This prior artpublication teaches the use of an alkoxide salt, a thioalkoxide salt ora hydrated sulfide salt for hydrolyzing the compound of formula 3 toobtain the corresponding thiocarboxylic acid, the compound of formula 4.The use of sodium hydrosulfide hydrate or sodium thiomethoxide ashydrolyzing agent for conversion of 17β-carboxylic acid to17β-carbothioic acid, via the intermediacy of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl derivative, has beenexemplified. However, sodium thiomethoxide is a corrosive and moisturesensitive reagent and use of sodium thiomethoxide would generate toxicmethyl mercaptan during acidification and sodium hydrosulfide isunstable and converts to sodium thiosulfate and sodium carbonate uponstorage. In the in-situ alkylation of sodium salt of compound of formula4, the excess sodium hydrosulfide would react with thechlorofluoromethane generating toxic and obnoxious organosulfurbyproducts, which can pose health hazards. Although isolation of thioicacid of formula 4 can be performed (by treatment with an acid) toovercome the problem, the excess sodium hydrosulfide would generatetoxic hydrogen sulfide. Further, the thiosulfate impurity which isinvariably present in sodium hydrosulfide, would generate sulfur uponacidification, which would contaminate the thioic acid and whose removalwould poses difficulties.

Some other shortcomings of this prior art method include (i) the longreaction time required for the alkylation reaction withchlorofluoromethane, about 22 hours. (ii) large molar excess ofchlorofluoromethane, requiring almost 7.5 molar equivalents, and (iii)handling difficulties with chlorofluoromethane, it being a gas. Incontrast in the process of the present invention the reaction of thioicacid of formula 4 is carried out using only 1.28 equivalents ofbromofluromethane, which is a liquid compound at below 15° C., for aperiod of about 2 hours only.

Gordon H. Phillipps et al, Journal of Medicinal Chemistry 37, 3717–3729(1994), disclose the method of preparing the compound of formula 1 bytreating a compound of formula 6 with carbonyldiimidazole undernitrogen, followed by a reaction with hydrogen sulfide to give thethioic acid of formula 7, which is isolated and treated with propionylchloride to give the compound of formula 4. This compound is thenalkylated with bromofluoromethane under nitrogen to yield the compoundof formula 1 in 69.3% yield. This reference does not mention thepreparation of compound of formula 1 directly from the compound offormula 3.

IL Patent No. 109656 discloses preparation of fluticasone propionate byesterification of compound of formula 4 with a halofluromethane,optionally in the presence of a catalyst such as tetrabutylammoniumbromide.

In one aspect the present invention provides a convenient process forpreparation of compound of formula 1, wherein an alkali metalcarbonate-alcohol system is used for the conversion of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene,a compound of formula 3 to6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid, a compound of formula 4 in contrast to prior art use of analkoxide, a thioalkoxide or hydrated sulphide salt (as in WO 01/62722)or use of amines such as diethylamine as in the '121 patent for thisreaction.

In another aspect the present invention provides an improved process forpreparation of compound of formula 1, wherein the compound of formula 2is treated with N,N-dimethylthiocarbamoyl chloride in an inert aproticsolvent to obtain compound of formula 3, which is reacted with ahydrosulfide reagent and bromofluoromethane to obtain compound offormula 1. The advantages include an improved yield, use of reagentsthat are easy to handle, low reaction time and use of lesser molaramounts of the reagents.

OBJECT OF THE INVENTION

The object of the present invention is to provide a facile, efficientand economic process for the preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate.

In particular, the process of the present invention provides a simpleand economical process wherein an alkali metal carbonate-alcohol systemis used for conversion of a compound of formula 3 to a compound offormula 4. Use of alkali metal carbonate-alcohol system providesimproved yield of the compound of formula 4, without contamination bysulfur or other sulfur containing byproducts.

The present invention also provides an improved process for preparationof compound of formula 1, wherein the compound of formula 2 is treatedwith N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent toobtain compound of formula 3, which is reacted with a hydrosulfidereagent and bromofluoromethane to obtain compound of formula 1. Theadvantages include an improved yield, use of reagents that are easy tohandle, low reaction time and use of lesser molar amounts of thereagents.

SUMMARY OF INVENTION

We have found a facile, efficient and economic process for thepreparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate(compound of formula 1) that provides an improved yield of the compound,using reagents that are easy to handle, utilizing a low reaction timeand using the reagents in lesser molar amounts.

In one aspect the present invention provides a process for thepreparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,a compound of formula 1, comprising

-   -   (a) treating the compound of formula 3 with an alkali metal        carbonate-alcohol system to obtain the compound of formula 4;    -   (b) reacting the compound of formula 4 with bromofluoromethane        to obtain the compound of formula 1.

In another aspect the present invention provides an improved process forthe preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,a compound of formula 1, comprising

-   -   (a) reacting        6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-dien-17β-carboxylic        acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl        chloride in an inert aprotic solvent in the presence of an        iodide catalyst and a base to give a compound of formula 3,    -   (b) reacting the compound of formula 3 with a hydrosulfide        reagent and bromofluromethane to obtain a compound of formula 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation ofS-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,a compound of formula 1, comprising

-   -   (a) treating the compound of formula 3 with an alkali metal        carbonate-alcohol system to obtain the compound of formula 4;    -   (b) reacting the compound of formula 4 with bromofluoromethane        to obtain the compound of formula 1.

In the process of the present invention the compound of formula 3 isconverted to a compound of formula 4 by treating with alkali metalcarbonate-alcohol system to generate the alkali metal salt of compoundof formula 4, viz., a compound of formula 4a, wherein M is the metal ioncorresponding to the alkali metal carbonate used, such as K, Na or Li.The compound of formula 4a can be neutralized in-situ by treatment withan acid to obtain the compound of formula 4. The compound of formula 4is then reacted with bromofluoromethane to obtain the compound offormula 1. It is also possible to convert the compound of formula 3 tothe compound of formula 1 directly in a one pot synthesis i.e. withoutisolating the compound of formula 4 by avoiding the reaction of compoundof formula 4a with the acid, and directly reacting the compound offormula 4a generated in-situ with bromofluoromethane to obtain thecompound of formula 1 (See Scheme 1).

The term “alkali metal carbonate”, as used herein, refers to potassiumcarbonate, sodium carbonate, cesium carbonate and the like. The term“acid”, as used herein, refers to reagents capable of donating protonsduring the course of the reaction. Examples of acids include mineralacids such as HCl, HBr, HI, sulfric acid, phosphoric acid and the like;organic acids such as acetic, formic, trifluoroacetic acid and the like;and sulfonic acids such as para-toluenesulfonic acid and the like.

Further in the process of the present invention for alkylating thecompound of formula 4, bromofluoromethane, which is a liquid at below15° C. is used, as compared to chlorofluoromethane, which is a gas, usedin the prior art process of WO 01/62722. The process of the presentinvention also utilizes lesser molar amounts of bromofluoromethane, ascompared to the excessive molar amounts of chlorofluoromethane requiredin the prior art process. Also, the alkylation with bromofluoromethanerequires shorter reaction time.

According to the process of the present invention, in step ‘a’ of theprocess, the compound of formula 3 is treated with alkali metalcarbonate-alcohol system to obtain the compound of formula 4.

Examples of alkali metal carbonate that can be used include sodiumcarbonate, potassium carbonate, cesium carbonate and the like. The mostpreferred alkali metal carbonate is potassium carbonate.

The mole ratio of the alkali metal carbonate to the compound of formula3 is between the range of 1:1 to 10:1. The preferred mole ratio is1.5:1.

In the process of the present invention the compound of formula 3 istreated with alkali metal carbonate-alcohol system. The term alcohol, asused herein is an organic compound containing a ‘hydroxyl’ group.Examples include alkanols, aromatic alcohols, phenols, glycols, diolsand the like. Preferably, the alcohol that may be used in the presentinvention has a boiling point greater than 55° C. under standardconditions of temperature and pressure. In a preferred embodiment thealcohol is an alkanol which may be any straight, branched or cyclic,substituted or unsubstituted, primary, secondary or tertiary alkanol ora mixture thereof. In a more preferred embodiment the alcohol is alinear alkanol containing 1 to 3 carbons. In a still more preferredembodiment the linear alkanol is methanol.

The compound of formula 3 is treated with alkali metal carbonate-alcoholsystem at temperature between the range of about 0° C. to about 100° C.,preferably between the range of about 20° C. to about 30° C.

In a preferred embodiment, the compound of formula 3 is treated withpotassium carbonate-methanol system.

In a preferred embodiment of the process of the present invention, thecompound of formula 3 is treated with potassium carbonate-methanolsystem at ambient temperature for about 3 hour to about 10 hours. Thereaction mixture is worked up by addition of water, followed by washingwith an organic solvent such as toluene. The separated aqueous layer isacidified with an acid such as HCl acid to pH of about 1.5 to about 2and the precipitated product is isolated.

In step ‘b’ of the process of the present invention, the compound offormula 4 is alkylated with bromofluoromethane. The compound of formula4 can be isolated and then treated with bromofluromethane to obtaincompound of formula 1. Alternately, it is also possible to directlyreact the in-situ formed salt of compound of formula 4 withbromofluromethane to obtain the compound of formula 1 in a one potsynthesis.

The mole ratio of bromofluoromethane to the compound of formula 4 may bein the range of about 1:1 to about 10:1. Preferably, the mole ratio ofbromofluoromethane to the compound of formula 4, used in the process ofthe present invention, is about 1.3:1.

The reaction of compound of formula 4 with bromofluoromethane is carriedout at a temperature below about 15° C., preferably between the range ofabout −5° C. to about 0° C. The reaction of compound of formula 4 withbromofluoromethane can be carried out in any polar protic or aproticsolvent. Examples of aprotic solvent are dimethylformamide,dimethylacetamide, dimethylsulfoxide and the like. Protic solvents likealkanols can also be used. Other polar solvents such as ketones, forexample, acetone, ethyl methyl ketone, isobutyl methyl ketone and thelike or nitriles, for example, acetonitrile can also be used. Thepreferred solvent for carrying out the reaction of compound of formula 4with bromofluoromethane is acetone.

The reaction of compound of formula 4 with bromofluoromethane is carriedout in presence of a suitable base such as an alkali metal carbonate oralkali metal bicarbonate. The preferred base is potassium carbonate orcesium carbonate, more preferred base is potassium carbonate.

In a preferred embodiment of the process of the present invention, thecompound of formula 3 is treated with potassium carbonate-methanolsystem at ambient temperature for about 3 hour to about 10 hour. Thereaction mixture is worked up by addition of water, followed by washingwith an organic solvent such as toluene. The separated aqueous layer isacidified with an acid such as HCl acid to pH of about 1.5 to about 2and the precipitated product is isolated to obtain a compound of formula4. The compound of formula 4 is reacted with bromofluoromethane inpresence of potassium carbonate in acetone at about 0° C. to about −5°C. for a period of about 3 hours to about 10 hours. The reaction isquenched by addition of water and the precipitated product is isolatedto obtain a compound of the formula 1.

It is also possible to prepare the compound of formula 1 by the processof the present invention wherein the compound of formula 3 is treatedwith an alkali metal carbonate-alcohol system to obtain the compound offormula 4a which is not treated with an acid but is converted tocompound of formula 1 directly by reaction with bromofluoromethane.

The compound of formula 1 may be purified by treatment with a solventsystem comprising one or more organic solvents selected from alcohols,esters, ethers, ketones, amides, nitrites, aliphatic or aromatichydrocarbons, halogenated hydrocarbons and mixtures thereof. The ratioof the organic solvent to the compound of formula 1 is in the range ofabout 1:1 to about 50:1.

In a preferred embodiment the compound of formula 1 is purified bytreatment with a solvent mixture of methanol:dichloromethane 1:1 v/v.

In the process of the present invention the compound of formula 3 whentreated with alkali metal carbonate-alcohol system such as potassiumcarbonate-methanol, will generate low levels of an ester impurity, suchas the methyl ester impurity, a compound of formula 8,

which can be detected by HPLC.

The compound of formula 3 can be prepared, for example, by reacting6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-dien-17β-carboxylicacid, a compound of formula 2, with N,N-dimethylthiocarbamoyl chloridein an inert aprotic solvent in the presence of an iodide catalyst and abase. In the prior art process of WO 01/62722 the compound of formula 2is reacted with N,N-dimethylthiocarbamoyl chloride in 2-butanone andsequentially treated with triethylamine, sodium iodide and water.However, the reaction mixture becomes unstirrable slurry after additionof sodium iodide and water. Whereas, in the process of the presentinvention it was observed that when the compound of formula 2 is reactedwith N,N-dimethylthiocarbamoyl chloride in tetrahydrofuran andsequentially treated with triethylamine and catalytic tetrabutylammonium iodide the reaction mixture remains clear.

In a preferred embodiment the compound of formula 3 is prepared byreacting a compound of formula 2 with N,N-dimethylthiocarbamoyl chloridein ether solvent, preferably tetrahydrofuran; in presence oftetrabutylammonium iodide catalyst and an organic base such astriethylamine, preferably at between about 0° C. to about 25° C.Preferably the mole ratio of the iodide catalyst to the compound offormula 2 is 0.1:1.

In another aspect the present invention provides an improved process forthe preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,a compound of formula 1, comprising

-   -   (a) reacting        6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-dien-17β-carboxylic        acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl        chloride in an inert aprotic solvent in the presence of an        iodide catalyst and a base to give a compound of formula 3,    -   (b) reacting the compound of formula 3 with a hydrosulfide        reagent and bromofluromethane to obtain a compound of formula 1.

The base selected may be inorganic or organic. Examples of inorganicbases that may be used in the present invention include hydrides,hydroxides, carbonates, or fluorides of alkali or alkaline earth metals.The organic base may be selected from secondary or tertiary amines andquaternary ammonium bases which may be cyclic or acyclic, Preferably,the organic base is selected from hindered acyclic or cyclic tertiaryamines and quaternary ammonium bases. In a preferred embodiment, anorganic base is used. Particularly preferred organic base istriethylamine.

The iodide catalyst may be an iodide salt selected from alkali metaliodides, alkaline earth metal iodides and quaternary ammonium iodides,the preferred catalyst being quaternary ammonium iodides, mostpreferably tetrabutylammonium iodide. The mole ratio of the catalyst to6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-dien-17β-carboxylicacid, the compound of formula 2 that may be used in the process of thepresent invention lies in the range of about 0.01:1 to about 0.5:1. Thepreferred mole ratio of the iodide catalyst:compound of formula 2 is0.1:1.

The reaction of a compound of formula 2 with N,N-dimethylthiocarbamoylchloride may be carried out in an inert aprotic solvent such asaliphatic or aromatic hydrocarbons, ethers, esters, nitrites and amides,or mixtures thereof. The preferred solvents are cyclic or acyclic etherssuch as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,tertbutyl methyl ether and the like or mixtures thereof; more preferablytetrahydrofuran is used as the solvent. The reaction of a compound offormula 2 with N,N-dimethylthiocarbamoyl chloride may be carried out attemperature ranging from about-10° C. to about 100° C., preferably fromabout 0° C. to about 25° C.

Preferably the compound of formula 3 is prepared by treating thecompound of formula 2 with N,N-dimethylthiocarbamoyl chloride intetrahydrofuran, in the presence of triethylamine and tetrabutylammoniumiodide at room temperature, followed by cooling to about 10–15° C. Thereaction mixture is warmed to ambient temperature and stirred for 2–8hours, preferably for 4 hours. At the end of the reaction, the reactionmixture is treated sequentially with a polar aprotic solvent and water.This polar aprotic solvent may be selected from dimethylformamide,dimethylacetamide and dimethyl sulfoxide and the like; the preferredsolvent being dimethylacetamide. The mixture is then cooled to 0° C.,stirred and the compound of formula 3 is isolated.

The compound of formula 3 is reacted with a hydrosulfide agent andbromofluoromethane to obtain the compound of formula 1. The hydrosulfidereagent may be selected from hydrated or anhydrous hydrosulfide salts,such as potassium hydrosulfide, sodium hydrosulfide, lithiumhydrosulfulfide, quaternary ammonium hydrosulfides and the like.Preferably, sodium hydrosulfide is used in the process of the presentinvention. The hydrosulfide salt may be taken in a suitable solventwhich facilitates nucleophilic substitution, such as dimethylformamide,dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide and thelike; the preferred solvent being dimethylacetamide.

The mole ratio of bromofluoromethane to the compound of formula 3 may bebetween the range of about 1:1 to about 5:1. Preferably, the mole ratioof bromofluoromethane to the compound of formula 3, used in the processof the present invention, is 3:1.

In a preferred embodiment of the process of the present invention, thecompound of formula 3 is treated with sodium hydrosulfide indimethylacetamide at low temperature, like 0° C., for about one hour toabout 6 hours, preferably for about 2 hours, followed by warming to roomtemperature and stirring for about one hour to about 5 hours, preferablyfor about 2 hours. The mixture is then cooled to below 0° C., like −2°C. to −10° C., preferably to about −5° C., and treated withbromofluoromethane. The reaction mixture is stirred further for abouthalf an hour to about 4 hours, preferably for about 1 hour. At the endof the reaction, the mixture is preferably stirred with an oxidizingagent such as aqueous sodium hypochloride, sodium chlorite, hydrogenperoxide, and the like, preferably aqueous hydrogen peroxide, in orderto oxidize other sulfide side products that may be formed during thereaction. The solid product is then filtered, washed with water anddried under vacuum to yield the compound of formula 1.

The compound of formula 2,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylicacid, may be prepared in conventional manner e.g. by oxidation of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3,20-dione-21-hydroxy-androsta-1,4-dienei.e. flumethasone, followed by reaction with propionyl chloride orpropionyl anhydride. The oxidation reaction may be carried out with asuitable oxidizing agent such as periodic acid.

Given below is the schematic representation of a preferred process bywhich a compound of the formula 2 may be prepared.

EXAMPLES Example 1 Preparation of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylicacid

A solution of periodic acid (83 g, 0.365 mole) in water (200 ml) isprepared by heating to 50–55° C. and cooling to 30–35° C. This solutionis added dropwise to a stirred suspension of flumethasone (100 g, 0.244mole) in tetrahydrofuran (400 ml) at 0–5° C. After completion ofaddition the mixture is stirred for further 2 hrs. at 0–5° C. andthereafter quenched by addition of water (600 ml) while maintainingtemperature at 5–15° C., then cooled to 0–5° C. and filtered. Theproduct6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylicacid is washed with water (˜2.0 ltr), and dried at 45–50° C. Yield 92.0g (95.3%, purity 99.55%).

Example 2 Preparation of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carboxylicacid, a compound of formula 2

To suspension of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylicacid (80 g, 0.202 mole) in acetone (400 ml) at 10–15° C. is addedsequentially triethylamine (85 ml, 0.606 mole) and propionic anhydride(78 ml, 0.606 mole). After stirring for 4 hrs. at 25–30° C.,diethylamine (42 ml, 0.404 mole) is added dropwise at 10–15° C. and thenstirred at ambient temperature for 1 hr. Thereafter the reaction mixtureis acidified to pH 1.0–1.5 at 0–5° C. The precipitated product isfiltered, washed with water, and dried at 4–45° C., until water contentis below 5%. Yield 90 g on dry basis (98.6%, purity>99.5%).

Example 3 Preparation of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene,a compound of formula 3

A solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carboxylicacid, (50.0 g, 110 mmol) and N,N-dimethylthiocarbamoyl chloride (27.4 g,222 mmol) in tetrahydrofuran (250 ml) at room temperature is cooled to10 to 15° C. It is sequentially treated with triethylamine (24.9 g, 244mmol) and tetrabutylammonium iodide (4.1 g, 11 mmol) at 10–15° C. Thereaction mixture is warmed to ambient temperature, stirred for 4 hrs andthen treated sequentially with dimethylacetamide (150 ml) and water (1.0lit). The resultant mixture is cooled to 0° C., stirred for 2 hours, andthe product is filtered. The solid obtained is washed with water (230ml) and dried at 55° C. for 4.0 hours to provide 57.0 g (96.0% yield,purity>98.5%) of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene.

Example 4 Preparation of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid, a compound of formula 4

A suspension of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene(20 g, 0.037 mol.) and potassium carbonate (10.23 g, 0.074 mol.) inmethanol (100 ml) is stirred at ambient temperature for 5 hrs under ablanket of nitrogen. Thereafter, water (100 ml) is added to the reactionmixture and the resultant clear solution is washed twice with toluene(40 ml). The aqueous layer containing the product is charcoalized (2 gcharcoal) at ambient temperature and then acidified with 2N HCl until pHis 1.5 to 2.0. The precipitated product is filtered, washed with water,and dried at 50–60° C. to obtain6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid (5) (yield 17.3 g, moisture content 3.3%, 96.33% on dry basis).

Example 5 Preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,compound of formula 1

A stirred mixture of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (5) (4 g, 0.0085 mol)) and anhydrous potassium carbonate (0.82 g,0.0059 mol.) in acetone (20 ml) under a blanket of nitrogen is cooled to0 to −5° C. and bromofluoromethane (1.05 g, 0.009 mol.) is added. Themixture is then stirred at 0 to −5° C. for further 5 hrs and thenquenched with water (20 ml). The precipitated product is filtered,washed with water (8 ml), and dried to obtain crude product (yield:3.625 g, moisture content 0.36%, 84.8%, purity 98.11%).

The crude fluticasone obtained as above is dissolved in 68 ml 1-butanolat 117–120° C. to get a clear solution (which may be optionallycharcoalized and filtered hot), and then gradually cooled to ambienttemperature for crystallization. The crystallized product is filtered.washed with 1-butanol (4 ml). Dried at 55–60° C. to obtain purefluticasone propionate (Yield 3.0 g, purity 99.24%).

Example 6 Preparation of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid

A suspension of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene(5.2 kg, 9.63 mol), and anhydrous potassium carbonate (2.0 kg, 14.47mol) in methanol (26 lit) is stirred at ambient temperature for 7 hrsunder blanket of nitrogen. Thereafter, water (26 lit) is added to thereaction mixture and the resulting clear solution is washed with toluene(16 lit). The aqueous layer containing product is then acidified with 6NHCl until pH is 1.5 to 2.0. The precipitated product is filtered, washedwith water, and dried at 50–60° C. to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid (yield 4.53 kg, water content 3.71%, theoretical yield 96.6%,purity 99.07%).

Example 7 Preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate[compound of formula 1, fluticasone propionate]

A stirred mixture of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid (25 g, 0.053 mol) and anhydrous potassium carbonate (6.0 g, 0.043mol) in acetone (125 ml) under a blanket of nitrogen is cooled to 0 to−5° C. and bromofluoromethane (7.53 g, 0.066 mol) is added. The mixtureis stirred at 0 to −5° C. for further 5 hrs and then quenched with water(125 ml), stirred for 30 min. The precipitated product is filtered,washed with acetone:water 1:1 mixture (2×40 ml), and dried to obtaincrude product (purity: 98.68%).

Purification Using 1-butanol-

The crude fluticasone (10 g) is dissolved in 1-butanol (200 ml) at115–120° C. Gradually cool to ambient temperature and stirred for 1 hr.The crystallized product is filtered and washed with 1-butanol (10 ml).Dried at 60–62° C. to obtain pure fluticasone propionate (recovery 8.5g, purity 99.40%).

Purification Using 1-butanol-methylene chloride-

The crude fluticasone (10 g) obtained as above is dissolved in mixtureof 1-butanol (110 ml) and methylene chloride (10 ml) under stirring atambient temperature and charcoalized. Recovered methylene chloride fromit under atmospheric pressure.

Gradually cool to 10° C. and stirred for 30 min. The crystallizedproduct is filtered and washed with 1-butanol (10 ml). Dried at 55–60°C. to obtain pure fluticasone propionate (recovery 9.0 g, purity99.35%).

Example 8 Preparation of Fluticasone Propionate on Kilogram Scale

A stirred mixture of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid (4.53 kg, 9.67 mol) and anhydrous potassium carbonate (1.09 kg,7.89 mol) in acetone (22.6 lit) under a blanket of nitrogen is cooled to0 to −5° C. Bromofluoromethane (1.40 kg, 12.40 mol) is then introduced,the reaction mixture is stirred at 0 to −5° C. for further 2 hrs andthen quenched with water (22.6 lit.), stirred for 60 min. Theprecipitated product is filtered, washed with water (9 lit), and driedto obtain crude product (Yield 4.66 kg, theoretical yield 96.28%).

Purification:

The fluticasone (4.66 kg) obtained as above is dissolved in mixture ofmethanol (45 lit) and dichloromethane (45 lit) under stirring at ambienttemperature and charcoalized. The methylene chloride is recovered (bydistillation) by distillation at atmospheric pressure. The mixture isthen gradually cooled to 10° C. and stirred for 60 min. The crystallizedproduct is filtered, washed with methanol (4.5 lit) and dried at 55–60°C. to obtain pure fluticasone propionate (Yield 4.09 kg, overall yield84.51%, purity 99.37%).

Example 9 One pot preparation of fluticasone propionate from17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-dieneand bromofluromethane using potassium carbonate-methanol system

A suspension of17β[(N,N-dimthylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene(5.0 g, 9.2 mmol) and anhydrous potassium carbonate (2.6 g, 18.8 mmol)in methanol (25 ml) is stirred at ambient temperature for 5.5 hrs underblanket of nitrogen. The suspension is cooled to 0 to −5° C. and addedbromofluoromethane (2.82 g, 24.95 mmol) and stirred for 7.5 hrs at 0° C.Methanol is recovered under reduced pressure at 50–55° C. and added 50ml DM water is added to the obtained residue, and stirred at ambienttemperature for 40 min. Slurry of the crude product filtered and driedin air oven at 50–60° C. Weight if the crude product: 4.26 g (Yield:91.85%, purity 96.53%).

Example 10 One pot preparation of fluticasone propionate from17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-dieneand bromofluromethane using hydrosulfide-dimethylacetamide system

A solution of17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene,compound of formula 3 (20.0 g, 37 mmol) and sodium hydrosulfide hydrate(9.4 g, 113 mmol) in dimethylacetamide (80 ml) at 0° C. is stirred undernitrogen blanketing for 2 hours; warmed to room temperature and againstirred for 2 hours. The mixture is then cooled to −5° C., treatedslowly with a solution of bromofluoromethane (12.6 g, 111 mmol) indimethylacetamide (25 ml), and stirred for 1 hour. A 5% aqueous solutionof hydrogen peroxide (40 ml) was added and the mixture stirred for 0.5hours at ambient temperature (reaction mixture should be positive tostarch iodide paper). It is then treated with a solution of sodiumbicarbonate (7.5 g) in water (375 ml) at −5° C., stirred for 1 hour, andfiltered to provide a solid. The solid is washed with water (250 ml) anddried at 55° C. under vacuum, to provide 20 g of crude compound offormula 1 (purity>97%).

Purification:

The compound of formula 1 obtained above is dissolved in ethyl acetate(0.8 lit.), stirred with 5% aqueous sodium carbonate solution (200 ml),and the mixture is filtered through Hyflo® bed. The aqueous layer isseparated out and back extracted with ethyl acetate (200 ml). Thecombined organic extracts are sequentially washed with water (250 ml),1.0N hydrochloric acid solution (200 ml), and water (200 ml). Theorganic layer is dried over anhydrous sodium sulfate, filtered through amicron filter (5 microns) and concentrated under reduced pressure at40–45° C. to ca. 60 ml. The suspension is refluxed for 30 min, graduallycooled to ambient temperature, stirred for 1 hour and the solid iscollected by filtration. The solid obtained is washed with chilled ethylacetate (30 ml, 10–15° C.) and dried at 45° C. under vacuum to provide15.5 g (85%) of compound of formula 1 meeting quality requirements asper British Pharmacopoeia.

Example 11

Given below in Table 1 is the result observed by monitoring the reactionby HPLC when17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene,compound of formula 3 is converted to6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid, compound of formula 4 in presence of an alkali metal carbonate (2mole equivalent) at ambient temperature in methanol (5 volumes).

TABLE 1 Potassium carbonate (K₂CO₃) Cesium carbonate (Cs₂CO₃) MethylMethyl ester ester Reaction impurity* impurity* time, Compd. of Compd.of (Compd. of Compd. of Compd. of (Compd. of hours formula 3* formula 4*formula 8) formula 3* formula 4* formula 8) 1 67.53 31.38 0.18 46.7350.96 0.85 2 42.52 55.94 0.31 27.5 69.35 1.28 3 20.38 75.21 0.58 11.4684.75 1.64 4 3.06 94.13 0.61 1.87 93.63 2.03 5 0.08 94.58 0.64 1.0594.13 2.23 *percentages as determined, from relative peak areas in HPLCchromatogram

1. A process for the preparation of S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate,the compound of formula 1, comprising (a) treating the compound offormula 3 with alkali metal carbonate-alcohol system to obtain thecompound of formula 4; (b) reacting the compound of formula 4 withbromofluoromethane to obtain the compound of formula 1,


2. The process as claimed in claim 1, wherein the alkali metal carbonateis potassium carbonate.
 3. The process as claimed in claim 1, whereinthe alcohol is an alkanol containing 1 to 3 carbons.
 4. The process asclaimed in claim 3, wherein the alcohol is a linear alkanol.
 5. Theprocess as claimed in claim 4, wherein the linear alkanol is methanol.6. The process as claimed in claim 1, wherein the mole ratio of alkalimetal carbonate to the compound of formula 3 is in the range of 1:1 to10:1.
 7. The process as claimed in claim 6, wherein the mole ratio ofalkali metal carbonate to the compound of formula 3 is 1.5:1.
 8. Theprocess as claimed in claim 1, wherein the compound of formula 3 istreated with alkali metal carbonate-alcohol system at a temperature inthe range of about 0° C. to about 100° C.
 9. The process as claimed inclaim 8, wherein the compound of formula 3 is treated with alkali metalcarbonate-alcohol system at a temperature in the range of about 20° C.to about 30° C.
 10. The process as claimed in claim 1, wherein reactionof the compound of formula 4 with bromofluoromethane is carried out at atemperature below about 15° C.
 11. The process as claimed in claim 10,wherein reaction of the compound of formula 4 with bromofluoromethane iscarried out at a temperature in the range of about −5° C. to about 0° C.12. The process as claimed in claim 1, wherein the alkali metalcarbonate-alcohol system is potassium carbonate-methanol.
 13. Theprocess as claimed in claim 1, wherein the mole ratio ofbromofluoromethane to the compound of formula 4 is in the range of 1:1to 10:1.
 14. The process as claimed in claim 13, wherein the mole ratioof bromofluoromethane to the compound of formula 4 is 1.3:1.
 15. Theprocess as claimed in claim 1, wherein reaction of the compound offormula 4 with bromofluoromethane is carried out in ketone solvent. 16.The process as claimed in claim 15, wherein the ketone solvent isacetone.
 17. The process as claimed in claim 1, wherein the compound offormula 3 is prepared by reacting6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, the compound of formula 2, withN,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in thepresence of an iodide catalyst and a base,


18. The process as claimed in claim 17, wherein the inert aproticsolvent is an ether and the mole ratio of the iodide catalyst to thecompound of formula 2 is 0.1:1.
 19. The process as claimed in claim 17wherein the inert aprotic solvent is tetrahydrofuran, the iodidecatalyst is tetrabutylammonium iodide, the base is triethylamine and thereaction is carried out at temperature in the range of about 0° C. toabout 25° C.